Disruption of MeCP2-TCF20 complex underlies distinct neurodevelopmental disorders

Proc Natl Acad Sci U S A. 2022 Jan 25;119(4):e2119078119. doi: 10.1073/pnas.2119078119.


MeCP2 is associated with Rett syndrome (RTT), MECP2 duplication syndrome, and a number of conditions with isolated features of these diseases, including autism, intellectual disability, and motor dysfunction. MeCP2 is known to broadly bind methylated DNA, but the precise molecular mechanism driving disease pathogenesis remains to be determined. Using proximity-dependent biotinylation (BioID), we identified a transcription factor 20 (TCF20) complex that interacts with MeCP2 at the chromatin interface. Importantly, RTT-causing mutations in MECP2 disrupt this interaction. TCF20 and MeCP2 are highly coexpressed in neurons and coregulate the expression of key neuronal genes. Reducing Tcf20 partially rescued the behavioral deficits caused by MECP2 overexpression, demonstrating a functional relationship between MeCP2 and TCF20 in MECP2 duplication syndrome pathogenesis. We identified a patient exhibiting RTT-like neurological features with a missense mutation in the PHF14 subunit of the TCF20 complex that abolishes the MeCP2-PHF14-TCF20 interaction. Our data demonstrate the critical role of the MeCP2-TCF20 complex for brain function.

Keywords: BioID; MeCP2; Rett syndrome; TCF20 complex; neurodevelopmental disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Biomarkers
  • Brain / metabolism
  • Disease Models, Animal
  • Disease Susceptibility
  • Methyl-CpG-Binding Protein 2 / genetics
  • Methyl-CpG-Binding Protein 2 / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Models, Biological
  • Multiprotein Complexes / metabolism*
  • Mutation
  • Neurodevelopmental Disorders / etiology*
  • Neurodevelopmental Disorders / metabolism*
  • Neurons / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Binding
  • Synapses / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Biomarkers
  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Multiprotein Complexes
  • Nuclear Proteins
  • PHF14 protein, human
  • Tcf20 protein, mouse
  • Transcription Factors